Project Summary/Abstract George C. Wang, MD, is an Instructor of Medicine in the Division of Geriatric Medicine at the Johns Hopkins University School of Medicine. His long-term career goal, as an independent clinical investigator, is to advance the understanding of the aging immune system and improve older adults' quality of life through improved vaccination and immunotherapeutic strategies. During the next five years of his career development, he aims to acquire mastery in tetramer-based enumeration of pathogen-specific CD8+ T-cell responses and the single-cell method of T-cell receptor (TCR) diversity analysis, and master epidemiologic skills in the analysis of longitudinal data nested within a large prospective cohort study. An interdisciplinary mentorship panel consisting of experts in aging, immunology, and epidemiology, and advanced extramural training in the immunology laboratory of Dr. Peter Doherty, Nobel laureate and T-cell viral immunity expert, at St. Jude Children's Research Hospital, will ensure the achievement of his goals. The aging-related accumulation of CD8+ clonal T cells, a significant proportion of which are specific for cytomegalovirus (CMV), an infection that has been associated with frailty in older adults, has been speculated to reduce overall TCR diversity and impairing the ability of older adults to mount responses to infections. Little is known about the longitudinal course of CMV-specific memory T cell and TCR diversity maintenance in humans, and its effect on the immune competence of the aging immune system and ultimately on the development of frailty in humans. In Specific Aim 1, Dr. Wang proposes to determine the longitudinal trajectory pattern of the CMV-specific frequencies of memory CD8+ T cells and TCR diversity at 5 distinct time points over a 12-year period, using repository peripheral blood mononuclear cell (PBMC) specimens from the Women's Health and Aging Study (WHAS) II. In Specific Aim 2, he proposes to determine longitudinally the effect of the immune response against CMV infection on the potential of CD8+ T-cell immunity to influenza, a contrasting acute infection with periodic antigenic boosting, by examining the longitudinal trajectory pattern of the influenza-specific frequencies of memory CD8+ T cells and TCR diversity, at 5 distinct time points over a 12-year period in WHAS II. In Specific Aim 3, he proposes to determine the temporal relationship between CMV-induced T-cell clonal expansions and degree of TCR diversity restriction and the onset and evolution of frailty in WHAS II. Results from these studies will substantially improve the understanding of long-term memory T cell maintenance in the aging immune system, and provide mechanistic and epidemiologic evidence of the role of CMV infection and restricted TCR diversity in the pathogenesis of reduced adaptive immune potential to infectious pathogens and of frailty in older adults. The long-term objective of this research plan is to enable the early identification of host factors and environmental exposures that render older adults most vulnerable to adverse health outcomes and frailty so that early preventative and therapeutic interventions can be instituted.